Process for the production of indole derivatives

ABSTRACT

The invention provides a process for the production of a compound of formula I, which comprises reacting a compound of formula II with a compound of formula III, in the presence of a strong base and a palladium(0) catalyst, at an elevated temperature, in a solvent which does not adversely affect the reaction. Compounds of formula I may be further processed to compounds of formula V, which are useful in the treatment of inter alia migraine.

This application is the National Stage application of Internationalapplication No. PCT/EP98/03996, filed Jun. 16, 1998, which claimspriority from Great Britain application No. 9714383.8, filed Jul. 8,1997.

This invention relates to a novel process for the production of a knownclass of compounds, some of which are known to be pharmacologicallyactive.

For example, International Patent Application WO 92/06973 discloses aseries of indole derivatives that are potent serotonin (5-HT) agonists.These compounds are indicated for treating disorders arising fromdeficient serotonergic neurotransmission comprising hypertension,depression, anxiety, eating disorders, obesity, drug abuse, clusterheadache, migraine, pain and chronic paroxysmal hemicrania and headacheassociated with vascular disorders. The compounds covered by WO 92/06973include(R)-5-(methylaminosulphonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(Example 5A, known as CP-122,288), which has the following structure:

UK Patent N^(o) 2,162,522 discloses an indole derivative (known assumatriptan) which is sold for the treatment of migraine under the trademark IMIGRAN, and which has the following structure:

European Patent Application 0548813 discloses another indole derivative(see Example 29, known as BMS-180048) which is indicated in thetreatment of migraine, and which has the following structure:

In the prior art, synthesis of these compounds begins with a substitutedbenzyl halide, which then undergoes displacement with a suitable sulphurnucleophile (for example sodium sulphite). The product is then oxidisedto the corresponding sulphonyl chloride and condensed with methylamineto give the desired secondary sulphonamide group. The resulting compoundthen undergoes an intramolecular cyclisation to form the desired indolering. In the case of CP-122,288, this cyclisation is a Heck reactionaccording to the following scheme:

wherein P is a protecting group.

Reactions of this type can have a low yield (often around 25%) andresult in a mixture of products, which require column chromatography topurify. This makes the production of the desired products expensive andinefficient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the process comprising the reaction of a cyano compoundof formula III with a halogen-substituted compound of formula II in thepresence of a strong base and palladium(0) catalyst to form a compoundof formula I followed by basic hydrolysis and decarboxylation to form acompound of formula IV which is then de-protected to form a compound offormula V.

FIG. 2 depicts a process for the preparation of compound of formula IIwherein R³ is a 3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]-propylgroup and R² is a CH₂OCH₂(C₆H₅) group.

The novel process of the present invention is summarised in accompanyingFIG. 1, in which R¹³ and Hal are defined below, and the compoundsdescribed above are compounds of formula V.

The process of the present invention utilises a palladium catalysedcross-coupling to introduce the sulphonamidomethylene unit in oneportion to a pre-formed indole ring, thus avoiding an intramolecularcyclisation and the problems associated with it, described above.Therefore the process of the present invention has the advantages thatit has a higher yield and does not always require column chromatography,in comparison with the prior art.

Sakamoto et al disclose palladium catalysed reactions ofphenylsulphonylacetonitrile with various halogen-substituted aromaticcompounds. The aromatic compounds concerned did not contain activehydrogen and so did not require protection during the reaction [seeSynthesis, 1992, p 552; and Chem Pharm Bull, 38(6), pp 1513-1517(1990)].

According to a first aspect of the present invention, there is provideda process for the production of a compound of formula I,

wherein R¹ and R² independently represent N-protecting groups; and

R³ represents a C₁₋₆ alkyl group substituted by:

(i) a 5- or 6-membered nitrogen-containing saturated heterocyclic groupwhich in turn may be substituted by C₁₋₆ alkyl or a pyrimidine ringwhich is itself substituted by C₁₋₆ alkoxy; or

(ii) di(C₁₋₆ alkyl)amino;

which comprises reacting a compound of formula II,

wherein Hal represents Cl, Br or I; and

R² and R³ are as defined above;

with a compound of formula III,

wherein R¹ is as defined above;

in the presence of a strong base and a palladium(0) catalyst, at anelevated temperature, in a solvent which does not adversely affect thereaction.

Preferred strong bases are sodium hydride and potassium t-butoxide.

Preferably, the palladium(0) catalyst istetrakis(triphenylphosphine)palladium(0). This may be added to thereaction mixture as Pd(II)Cl₂[P(C₆H₅)₃]₂, and is converted to thepalladium(0) species under the reaction conditions. Similarly,Pd(II)(O₂CCH₃)₂ may be added to the reaction mixture and is converted toa palladium(0) species under the reaction conditions.

Suitable solvents include toluene, and, more preferably, a mixture oftoluene and ethylene glycol-dimethylether (CH₃OCH₂CH₂OCH₃). This lattersolvent system has the advantage that the deprotonated compounds offormula III remain mobile in the reaction mixture and so available forreaction.

Preferably, the process is carried out at the reflux temperature of thesolvent. In the solvent systems mentioned in the preceding paragraph,this will be approximately 80° C. and 100° C. respectively. At thesetemperatures, the process should be complete in 1-3 hours.

Preferably, Hal is Br.

According to a second aspect of the present invention, there is provideda process for the production of a compound of formula V,

wherein

R³ is as defined above;

which comprises:

(i) basic hydrolysis of the cyano group of a compound of formula I asdefined above, followed by decarboxylation of the resulting carboxylicacid, to provide a compound of formula IV,

wherein R¹⁻³ are as defined above; followed by

(ii) replacement of R¹ and R² with H.

Preferably, step (i) is carried out using aqueous potassium hydroxide inethanol at an elevated temperature. The aqueous potassium hydroxide ispreferably dilute (for example 1-2 M). The reaction is preferablycarried out at the reflux temperature of the reaction mixture (typicallyaround 78° C. using the preferred conditions mentioned above). Underthese conditions, the reaction is usually complete in 8-16 hours.

Preferably, R¹ and R² are replaced with H under the same conditions instep (ii), but they may be replaced sequentially. A preferred method fortheir simultaneous replacement is hydrogenolysis. Suitablehydrogenolysis conditions include palladium-on-carbon in the presence ofhydrogen gas at a temperature of 60° C. and a pressure of 414 kPa (60psi); and sodium or calcium in liquid ammonia at −50 to −33° C.

In each aspect of the invention, it is preferred that R¹ representsbenzyl, CH₂OCH₂(C₆H₅), CH(C₆H₅)₂ or t-butyl. CH₂OCH₂(C₆H₅) is ofparticular interest.

In each aspect of the invention, it is preferred that R² represents anN-protecting group which is stable to basic hydrolysis conditions,particularly the basic hydrolysis conditions used in step (i) of thesecond aspect of the invention. It has been found that the basichydrolysis and decarboxylation of this step is greatly enhanced if R²remains in place during the reaction. Of course, R² need not be the samein each aspect of the invention, but selection of a suitable R² group incompounds of formula II in the first aspect of the invention obviatesthe need to replace an unstable protecting group for step (i) of thesecond aspect of the invention, so that the enhancement mentioned abovecan be achieved. N-protecting groups that are stable to basic hydrolysisconditions include benzyl, CH₂OCH₂(C₆H₅), CH₂OCH₂CH₂Si(CH₃)₃ andCH₂CHCH₂. However, since they are both removable by hydrogenolysis,benzyl and CH₂OCH₂(C₆H₅) are preferred.

Preferably, R³ represents CH₂CH₂N(CH₃)₂ or a group of formula Ia or Ib,

The compounds of formula V in which R³ represents these groups aresumatriptan, CP-122,288 and BMS-180048 respectively.

The invention further provides the intermediate compounds of formulae I,III and IV as defined above.

Compounds of formulae II and III may be prepared by conventional methodsas illustrated in the examples. When R³ is a group of formula Ib and R²represents CH₂OCH₂(C₆H₅), the compound of formula II may be prepared asshown in accompanying FIG. 2.

The invention is illustrated by the following Examples, in which theabbreviations set out below may be used:

DMF dimethylformamide Et ethyl IMS industrial methylated spirits hr hourMeOH methanol min minute LRMS low resolution mass spectroscopy THFtetrahydrofuran

EXAMPLE 1(R)-N-Methyl-[3-(1-methyl-2-pyrrolidinylmethyl-1H-indol-5-yl]methanesulfonamide

(a) Methyl (N-benzyl-N-methylsulfamoyl)acetate

To a stirred solution of N-methyl benzylamine (7 ml, 54.2 mmol) indichloromethane (10 ml) at 0-5° C. under an atmosphere of nitrogen wasadded dropwise a solution of methyl chlorosulfonylacetate (prepared bythe method of M. J. Szymonifka and J. V. Heck, Tetrahedron Lett., 1989,30, 22, 2869) (4.26 g, 24.7 mmol) in dichloromethane (5 ml), maintainingthe temperature below 5° C. The yellow solution was then warmed toambient temperature over a 2 hr period before water (30 ml) was added.The organic phase was partitioned and evaporated in vacuo to give ayellow oil. This was purified by flash column chromatography (diethylether:hexane 1:1 as eluant) to give the subtitle compound (3.9 g, 61%)as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ=2.83 (3H, s), 3.83 (3H, s), 4.02 (2H, s), 4.38(2H, s), 7.27-7.42 (5H, m).

Found: C, 51.31; H, 5.92; N, 5.42. C₁₁H₁₅NO₄S requires C, 51.35; H,5.88; N, 5.44%.

(b) (N-Benzyl-N-methylsulfamoyl)acetamide

To a stirred solution of methyl (N-benzyl-N-methylsulfamoyl)acetate(from step (a), 3.9 g, 15.2 mmol) in tetrahydrofuran (10 ml) at ambienttemperature was added aqueous ammonia (10 ml, s.g.=0.88) in one portion.The orange solution was then stirred at ambient temperature for 18 hr,before being poured into water (50 ml) and extracted with ethyl acetate(3×25 ml). The organic extract was evaporated in vacuo to give thesubtitle compound (2.8 g, 76%) as a white solid. m.p. 124-127° C.

¹H NMR (300 MHz, CDCl₃) δ=2.83 (3H, s), 3.92 (2H, s), 4.39 (2H, s), 5.61(1H, bs), 6.50 (1H bs), 7.20-7.45 (5H, m).

Found: C, 49.56; H, 5.78; N, 11.54. C₁₀H₁₄ N₂O₃S requires C, 49.57; H,5.82; N, 11.56%.

(c) N-Benzyl-1-cyano-N-methylmethanesulfonamide

The subtitle compound (2.36 g, 91%) was prepared as a white solid from(N-benzyl-N-methylsulfamoyl)acetamide (from step (b), 2.8 g, 11.6 mmol)according to the procedure of Bargar and Riley (SyntheticCommunications, 1980, 10 (6), 479). m.p. 68-70° C. ¹H NMR (300 MHz,CDCl₃) δ=2.95 (3H, s), 3.96 (2H, s), 4.50 (2H, s), 7.10-7.53 (5H, m).

Found: C, 53.41; H, 5.36; N, 12.39. C₁₀H₁₂N₂O₂S requires C, 53.55; H,5.39; N, 12.49%.

(d) (R)-1-Benzyl-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole

To a stirred solution of(R)-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (see Example 27,WO 92/06973) (21.44 g, 73.2 mmol) in tetrahydrofuran (110 ml) at 0° C.under a nitrogen atmosphere was added sodium hydride (60% dispersion inmineral oil, 3.51 g, 87.7 mmol) portionwise, maintaining the temperaturebelow 5° C. Upon completion of the addition, the dark brown solution wasstirred at 0-5° C. for 1 hr before benzyl bromide (10.4 ml, 87.4 mmol)was added dropwise maintaining the temperature below 5° C. The brownsolution was then warmed to ambient temperature over a 1 hr periodbefore being quenched into water (100 ml). The mixture was thenextracted with ethyl acetate (3×25 ml) and the organic extracts werecombined and evaporated in vacuo to yield a brown oil. This was purifiedby flash column chromatography (ethyl acetatehexane:diethylamine 1:1:0.1as eluant) to give the subtitle compound (17.6 g, 63%) as a brownviscous oil.

¹H NMR (300 MHz, CDCl₃) δ=1.50-1.95 (4H, m), 2.19-2.35 (1H, m), 2.49(4H, m), 2.56-2.70 (1H, m), 3.10-3.25 (2H, m), 5.20 (2H, s), 6.99 (1H,s), 7.03-7.16 (3H, m), 7.20-7.37 (4H, m), 7.69 (1H, s).

Found: C, 65.83; H, 6.08; N, 7.24. C₂₁H₂₃BrN₂ requires C, 65.80; H,6.05; N, 7.31%. [α]_(D)+64.30° (c=1.78, MeOH).

(e)N-Benzyl-1-[(R)-1-benzyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-1-cyano-N-methylmethanesulfonamide

To a stirred solution of N-benzyl-1-cyano-N-methylmethanesulfonamide(from step (c), 643 mg, 2.9 mmol) in toluene (5 ml) at 0° C. under anitrogen atmosphere was added potassium tert-butoxide (615 mg, 5.5 mmol)portionwise, maintaining the temperature below 5° C. The brown solutionwas then warmed to ambient temperature over a 10 min period, beforetetrakis(triphenylphosphine) palladium(0) (181 mg, 0.16 mmol) was addedin one portion. A solution of(R)-1-benzyl-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (fromstep (d), 1.0 g, 2.6 mmol) in toluene (5 ml) was then added dropwise tothe yellow slurry and the mixture was warmed to reflux. Reflux wasmaintained for 1.5 hr after which time the dark brown solution wascooled to ambient temperature. The reaction mixture was then poured intowater (25 ml) and extracted with ethyl acetate (3×25 ml). The combinedorganic extracts were evaporated in vacuo to yield a brown oil. This waspurified by flash column chromatography (ethylacetate:hexane:diethylamine 1:1:0.1 as eluant) to give the titlecompound (1.09 g, 80%) as a brown oil.

¹H NMR (300 MHz, CDCl₃) δ=1.49-1.90 (4H, m), 2.16-2.30 (1H, m),2.35-2.55 (4H, m), 2.62-2.81 (4H, m), 3.08-3.26 (2H, m), 4.18 (2H, s),5.26 (1H, s), 5.31 (2H, s) 7.02-7.13 (3H, m), 7.20-7.41(10H, m),7.81(1H, bs).

Found: C, 69.94; H, 6.56; N, 10.23. C₃₁H₃₄ N₄O₂S requires C, 70.7; H,6.51; N, 10.64%.

(f)(R)-N-Benzyl-1-[1-benzyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-N-methylmethanesulfonamide

To a stirred solution ofN-benzyl-1-[(R)-1-benzyl-3-(1-methyl-2-pyrrolidinylethyl)-1H-indol-5-yl]-1-cyano-N-methylmethanesulfonamide(from step (e), 29 g, 55.1 mmol) in ethanol (200 ml) at ambienttemperature was added 2N potassium hydroxide solution (200 ml, 400mmol). The dark brown solution was then brought to reflux and maintainedat this temperature for 15 hr. The oily reaction mixture was then cooledto ambient temperature and extracted with ethyl acetate (3×300 ml). Theorganic extracts where combined and evaporated in vacuo to give a darkbrown oil. This was purified by flash column chromatography (ethylacetate:hexane:diethylamine 1:1:0.1 as eluant) to yield the subtitlecompound (24.67 g, 89%) as a brown oil.

¹H NMR (300 Mhz, CDCl₃) δ=1.54-1.98 (4H, m), 2.18-2.35 (1H, m),2.40-2.86 (8H, m), 3.09-3.30 (2H, m), 4.03 (2H, s), 4.42 (2H, s), 5.28(2H, s) 6.99-7.44 (13H, m), 7.64 (1H, s).

Found: C, 70.99; H, 7.07; N, 8.10. C₃₀H₃₅N₃O₂S requires C, 71.82; H,7.04; N, 8.38%. [α]_(D) +50.98° (c=1.55, CH₂Cl₂.

(g)(R)-N-Methyl-[3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]methanesulfonamide

A solution of(R)-N-Benzyl-1-[1-benzyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-N-methylmethanesulfonamide(from step (f), 2.04 g) in tetrahydrofuran (2 ml) was added dropwise toliquid ammonia (10 ml) at −40° C. under a nitrogen atmosphere. Sodium(approximately 500 mg) was then added portionwise to the colourlesssolution, until a permanent dark blue coloured solution was obtained.The blue solution was stirred for a further 30 min at −40° C. beforesaturated ammonium chloride solution (5 ml) was added and the greyslurry warmed to ambient temperature over an 8 hr period. The whiteslurry was then diluted with water (10 ml), filtered and dried in vacuoat 50° C. to give the title compound (733 mg, 56%) as a white solid.m.p. 209-213° C.

¹H NMR (300 MHz, DMSO) δ=1.36-1.81 (4H, m), 2.04-2.17 (1H, m), 2.28-2.52(8H, m), 2.90-3.09 (2H, m), 4.34 (2H, s), 6.74-6.83 (1H, m), 7.07 (1H,d, J=9.7 Hz), 7.15 (1H, bs), 7.30 (1H, d, J=9.7 Hz), 7.51 (1H, s), 10.85(1H, bs). LRMS (Thermospray): 322 (MH⁺). [α]_(D) +81.08° (c=0.47, DMSO).

EXAMPLE 2(R)-N-Methyl-[3-(1-methyl-2-pyrrolidinylmethyl)1H-indol-5yl]methanesulfonamide(Alternative route)

(a) Methyl (N-diphenylmethyl-N-methylsulfamoyl)acetate

The subtitle compound (3.05 g, 37%) was prepared as a clear brown oilfrom N-methyl benzhydrylamine (prepared according to the method of Z.Horii, T Sakai and Inoi, Pharm Bull., 1955, 3, 159) (10.7 g, 50.7 mmol)and methyl chlorosulfonylacetate (4.27 g, 24.7 mmol), using the methodof Example 1(a).

¹H NMR (300 MHz, CDCl₃) δ=2.84 (3H, s), 3.72 (3H, s), 3.82 (2H, s), 6.43(1H, s) 7.10-7.47(10H, m).

Found: C, 61.29; H 5.74; N, 4.21. C₁₇H₁₉O₄NS requires C, 61.24; H 5.74;N, 4.20%.

(b) (N-Diphenylmethyl-N-methylsulfamoyl)acetamide

The subtitle compound (2.62 g, 90%) was prepared as a white solid fromaqueous ammonia solution (10 ml, s.g.=0.88) and methyl(N-diphenylmethyl-N-methylsulfamoyl)acetate (from step (a), 3.05 g, 9.2mmol), using the method of Example 1(b). m.p. 110-115° C.

¹H NMR (300 MHz, CDCl₃) δ=2.80 (3H, s), 3.72 (2H, s), 5.63 (1H, bs),6.41 (1H, s), 6.60 (1H, bs), 7.05-7.48 (10H, m).

Found: C, 60.13; H 5.67; N, 8.75. C₁₆H₁₈N₂O₃S requires C, 60.36; H 5.77;N, 8.80%.

(c) 1-Cyano-N-diphenylmethyl-N-methylmethanesulfonamide

The subtitle compound (0.7 g, 71%) was prepared as a beige solid from(N-Diphenylmethyl-N-methylsulfamoyl)acetamide (from step (b), 1.0 g,3.14 mmol) using the method of Example 1(c). m.p. 104-107° C.

¹H NMR (300 MHz, CDCl₃) δ=2.98 (3H, s), 3.71 (2H, s), 6.39 (1H, s),7.20-7.46 (10H, m).

Found: C, 63.94; H, 5.38; N, 9.24. C₁₆H₁₆N₂O₂S requires C, 63.98; H,5.37; N, 9.33%.

(d)1-[(R)-1-Benzyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide

To a stirred solution of1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide (from step (c),18.79 g, 62.6 mmol) in a mixture of toluene (60 ml) and ethylene glycoldimethylether (20 ml) at 0-5° C. under a nitrogen atmosphere was addedsodium hydride (60% dispersion in mineral oil) (4.6 g, 115 mmol)portionwise, maintaining the temperature below 5° C. Upon completion ofthe addition, the dark brown solution was warmed to ambient temperatureover a 30 min period, before tetrakis(triphenylphosphine) palladium(0)(3.61 g, 3.1 mmol) was added in one portion. A solution of(R)-1-benzyl-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (fromExample 1(d), 19.74 g, 52 mmol) in toluene (20 ml) was then addeddropwise to the brown slurry and the mixture was warmed to reflux.Reflux was maintained for 2 hr after which time the dark brown solutionwas cooled to ambient temperature. The reaction mixture was then pouredinto water (250ml) and extracted with ethyl acetate (3×100 ml). Theorganic extracts were combined and evaporated in vacuo to yield a brownoil. This was re-dissolved in absolute ethanol (80 ml) and stirred for18 hr over which time precipitation occurred. The solid seas filteredand dried in vacuo at 50° C. overnight to yield the subtitle compound(22 g, 70%) as a cream solid. m.p. 152-155° C.

¹H NMR (300 MHz, CDCl₃) δ=1.38-1.91 (4H, m), 2.14-2.30 (1H, m),2.35-2.50 (4H, m), 2.55-2.70 (1H, m), 2.78 (3H, s), 3.02-3.20 (2H, m),4.98 (1H, s), 5.28 (2H, s), 6.41 (1H, s), 6.89-7.53 (18H, m), 7.60 (1H,bs).

Found: C, 73.70; H, 6.28; N, 9.26. C₃₇H₃3 N4O₂S requires C, 73.72; H,6.35; N, 9.29%.

(e)(R)-1-[1-Benzyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-N-diphenylmethyl-N-methylmethanesulfonamide

To a stirred solution of1-[(R)-1-benzyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide(from step (d), 11.61 g, 19.3 mmol) in ethanol (35 ml) at ambienttemperature was added 2N potassium hydroxide solution (35 ml, 70 mmol).The dark brown solution was then brought to reflux and maintained atthis temperature for 15 hr. The oily reaction mixture was then cooled toambient temperature and extracted with ethyl acetate (3×100 ml). Theorganic extracts were combined and evaporated in vacuo to yield thecrude product as a dark brown oil. The oil was diluted with ethanol (35ml) and stirred at ambient temperature for 12 hr, which resulted inprecipitation. The mixture was then filtered and the solid dried invacuo at 50° C. overnight to yield the title compound (6.82 g, 61%) as abeige solid. m.p. 117-120° C.

¹H NMR (300 MHz, CDCl₃) δ=1.48-1.95 (4H, m), 2.16-2.32 (1H, m),2.39-2.70 (8H, m), 3.05-3.25 (2H, m), 4.24 (2H, s), 5.26 (2H, s), 6.36(1H, s) 6.90-7.49 (19H, m).

Found: C, 74.40; H, 6.75; N, 7.34. C₃₆H₃₉N₃O₂ S requires C, 74.80; H.6.76; N, 7.27%. [α]_(D)=+50.79 (c=1.8, CH₂Cl₂).

(f)(R)-N-Methyl-[3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]methanesulfonamide

Into a stirred slurry of calcium tunings (1.11 g, 27.7 mmol) intetrahydrofuran (1.2 ml) at −40° C. was added condensed liquid ammonia(16 ml). The blue bronze was stirred at −50 to −40° C. for a further 15min, before a solution of(R)-1-[1-benzyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-N-diphenylmethyl-N-methylmethanesulfonamide(from step (e), 4.0 g, 6.93 mmol) in tetrahydrofuran (10 ml) was addeddropwise, maintaining the temperature below −40° C. The dark bluesolution was stirred at −40° C. for a further 30 min, before saturatedammonium chloride solution (10 ml) was added dropwise and the greysolution warmed to ambient temperature. Water (10 ml) was then added andthe white slurry stirred for 15 min, before being filtered in vacuo. Thesolid was then dissolved in 5N HCl (12 ml) and the resulting orangesolution extracted with ethyl acetate (10 ml). The pH of the aqueousphase was then adjusted (pH=10) with 10N NaOH which resulted inprecipitation. The solid was filtered and dried in vacuo at 50° C.overnight to yield the title compound (1.54 g, 73%) as a white solid.m.p. 209-212° C.

¹H NMR (300 MHz, DMSO) δ=1.36-1.81 (4H, m), 2.04-2.17 (1H, m), 2.28-2.52(8H, m), 2.90-3.09 (2H, m), 4.34 (2H, s), 6.74-6.83 (1H, m), 7.07 (1H,d, J=9.7 Hz), 7.15 (1H, bs), 7.30 (1H, d, J=9.7 Hz), 7.51 (1H, s), 10.85(1H, bs). LRMS (Thermospray): 322 (MH³⁰ ).

EXAMPLE 3(R)-N-Methyl-[3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]methanesulfonamide(Alternative route)

(a) (N-Methylsulfamoyl)acetamide

A solution of (N-benzyl-N-methylsulfamoyl)acetamide (see Example 1(b),13.0 g, 50.5 mmol) in methanol (130 ml) was hydrogenated over Pearlman'scatalyst (7.5 g) at 60° C. and at 345 kPa (50 psi) for 24 hr. Thesolution was then filtered through a pad of celite (trade mark) whichwas subsequently washed with acetone (50 ml). The combined filter wasevaporated in vacuo to give a white solid which was dried in vacuo at50° C. overnight to yield the subtitle compound (8.0 g, 98%) as a whitesolid. m.p. 104-108° C.

¹H NMR (250 MHz, DMSO) δ=2.55-2.65 (3H, d, J=4.9 Hz), 3.85 (2H, s),6.88-7.05 (1H, m), 7.32 (1H, bs), 7.60 (1H, bs). LRMS (Thermospray)169.7 (MNH₄ ⁺).

(b)) 1-Cyano-N-methylmethanesulfonamide

The subtitle compound (0.87 g, 99%) was prepared as a beige solid from(N-methylsulfamoyl)acetamide (from step (a), 1.0 g, 6.57 mmol) by themethod of Example 1(c). m.p. 36-39° C.

¹H NMR (300 MHz, DMSO) δ=2.65 (3H, s), 4.75 (2H, s), 7.85 (1H, bs). LRMS(Thermospray) 152.0 (MH⁺).

(c) N-Benzyloxymethy-1-cyano-N-methylmethanesulfonamide

To a stirred solution of 1-cyano-N-methylmethanesulfonamide (from step(b), 250 mg, 1.9 mmol) in tetrahydrofaran (5 ml) at 0-5° C. under anatmosphere of nitrogen was added sodium hydride (60% dispersion inmineral oil, 75 mg, 1.9 mmol) in one portion. The resulting slurry wasstirred at 0-5° C. for 45 min, before benzyloxymethyl chloride (80%purity, 0.368 g, 1.9 mmol) in tetrahydrofuran (5 ml) was added dropwiseover a 15 min period. The mixture was then allowed to warm to ambienttemperature over a 3 hr period. The solvents were then evaporated invacuo and the resulting oil was purified by flash column chromatography(diethyl ether:hexanes 3:1 as eluant) to yield the subtitle compound(296 mg, 61.6%) as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ=3.19 (3H, s), 4.05 (2H, s), 4.62 (2H, s), 4.81(2H, s), 7.29-7.50 (5H, m). LRMS (Thermospray) 272.3 (MNH₄ ⁺).

(d)(R)-1-Benzyloxnmethyl-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole

To a stirred suspension of potassium tert-butoxide (5.5 g, 45 mmol) intetrahydrofuran (30 ml) at 0-5° C. under a nitrogen atmosphere was addeda solution of (R)-5-bromo-3(1-methyl-2-pyrrolidinylmethyl)-1H-indole (12g, 41 mmol) in THF (40 ml) dropwise, maintaining the temperature below10° C. Upon completion of the addition, the dark brown solution wasstirred at 0-5° C. for 1 hr before benzylchloromethylether (80% purity,8.8 g, 45 mmol) was added dropwise maintaining the temperature below 5°C. The brown solution was then warmed to ambient temperature over a 1 hrperiod before being quenched into water (100 ml). The mixture was thenextracted with ethyl acetate (3×25 ml) and the combined organic phaseswere evaporated in vacuo to yield a brown oil. This was purified byflash column chromatography (ethyl acetate:triethylamine 100:5 aseluant) to give the subtitle compound (14.1 g, 83%) as a brown oil.

¹H NMR (300 MHz, CDCl₃) δ=1.42-1.95 (4H, m), 2.11-2.32 (1H, m),2.32-2.65 (5H, m), 3.0-3.20 (2H, m), 4.36 (2H, s), 5.48 (2H, s), 7.01(1H, s), 7.13-7.42 (7H, m), 7.72 (1H, s). LRMS (Thermospray): 413.3(MH⁺)

(e)N-Benzyloxymetyl-1-[(R)-1-benzyloxymethyl-3-(1-methyl-2-pyrrolidinalmethy)-1H-indol-5-yl]-1-cyano-N-methylmethanesulfonamide

To a stirred suspension of sodium hydride (60% dispersion in mineraloil, 470 mg, 11.7 mmol) and tetrakis(triphenylphosphine) palladium(0)(370 mg, 0.32 mmol) in a mixture of toluene (5 ml) and ethylene glycoldimethylether (1.62 ml) under a nitrogen atmosphere was added a solutionof N-benzyloxymethyl-1-cyano-N-methylmethanesulfonamide (from step (c),1.62 g, 6.4 mmol) in toluene (2.2 ml) at 0-5° C. The mixture was thenwarmed to ambient temperature and stirred for 30 min, before a solutionof(R)-1-benzyloxymethyl-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole(from step (d), 2.2 g, 5.3 mmol) in toluene (2.2 ml) was added in oneportion and the mixture was warmed to reflux. Reflux was maintained for2 hr after which time the dark brown solution was cooled to ambienttemperature. The reaction mixture was then poured into water (20 ml) andextracted with ethyl acetate (3×15 ml). The organic extracts werecombined and evaporated in vacuo to yield a brown oil. This was purifiedby flash column chromatography (ethyl acetate:triethylamine 97.5:2.5) togive the subtitle compound (2.98 g, 95%) as a brown oil.

¹H NMR (300 MHz, CDCl₃) δ=1.46-1.95 (4H, m), 2.15-2.30 (1H, m),2.37-2.75 (5H, m), 3.02 (3H, s), 3.05-3.20 (2H, m), 4.40 (3H, s),4.47-4.62 (4H, m), 5.31 (1H, s), 5.50 (2H, s), 7.08 (1H, s), 7.20-7.81(13H, m). LRMS (Thermospray): 586.7 (MH⁺).

(f)(R)-N-Benzyloxymethyl-1-[1-benzyloxymethyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-N-methylmethanesulfonamide

To a stirred solution ofN-benzyloxymethyl-1-[(R)-1-benzyloxymethyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-1-cyano-N-methylmethanesulfonamide(from step (e), 2.0 g, 3.4 mmol) in IMS (14 ml) at ambient temperaturewas added 2N potassium hydrodroxide solution (7 ml, 14 mmol). The darkbrown solution was then brought to reflux and maintained at thistemperature for 15 hr. The oily reaction mixture was then cooled toambient temperature and extracted with ethyl acetate (3×20 ml). Theorganic extracts were combined and evaporated in vacuo to yield a darkbrown oil. This was purified by flash column chromatography (ethylacetate:triethylamine 95:5 as eluant) to yield the subtitle compound(631 mg, 33%) as a brown oil.

¹H NMR (300 MHz, CDCl₃) 1.46-1.94 (4H, m), 2.16-2.32 (1H, m), 2.37-2.75(5H, m), 2.89 (3H, s), 3.05-3.23 (2H, m), 4.3-4.52 (10H, m), 5.51 (2H,s), 6.93-7.66 (14H, m). LRMS (Thermospray): 562.5 (MH⁺).

(g)(R)-N-Methyl-[3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]methanesulfonamide

A mixture of(R)-N-Benzyloxymethyl-1-[1-benzyloxymethyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-N-methylmethanesulfonamide(from step (f), 300 mg, 0.5 mmol) and methanesulfonic acid (60 mg, 0.6mmol) in water (5 ml) was hydrogenated over Pearlman's catalyst (300 mg)at 60° C. and at 345 kPa (50 psi) for 18 hr. The solution was thenfiltered through a pad of celite (trade mark) and the filtrate waspartitioned between saturated sodium bicarbonate (25 ml) anddichloromethane (3×50 ml). The combined organic extract was thenevaporated in vacuo and the residue was dissolved in a mixture of THFand water (1:1) (10 ml). A solution of Triton B (40% w.w. in methanol)(0.2 ml, 0.44 mmol) was then added dropwise and the solution was thenrefluxed for 2 hr. The solution was then cooled to ambient temperaturebefore being poured into water (10 ml) and extracted withdichloromethane (3×25 ml). The combined organic extracts were evaporatedin vacuo to give a yellow film. This was then triturated with IMS (5 ml)and tie solid was filtered in vacuo and dried at 50° C. overnight toyield the title compound (50 mg, 29%) as a white solid. m.p. 209-231° C.

¹H NMR (300 MHz DMSO) δ=1.36-1.81 (4H, m), 2.04-2.17 (1H,m), 2.28-2.52(8H, m), 2.90-3.09 (2H, m), 4.34 (2H, s), 6.74-6.83 (1H, m), 7.07 (1H,d, J=9.7 Hz), 7.15 (1H, bs), 7.30 (1H, d, J=9.7 Hz), 7.51 (1H, s), 10.85(1H, bs). LRMS (Thermospray): 322 (MH⁺).

EXAMPLE 4(R)-N-Benzyl-N-methyl-1-[3-(1-methyl-2-pyrrolidinylmethyl)-1-trimethysilyethyloxmethyl-1H-indol-5-yl]methanesulfonamide

(a)(R)-5-Bromo-3-1-methyl-2-pyrrolidinylmethyl)-1-trimethsilylethyloxymethyl-1H-indole

To a stirred solution of(R)-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (10 g, 34.lmmol)in tetrahydrofuran (100 ml) at 0° C. under a nitrogen atmosphere wasadded sodium hydride (60% dispersion in mineral oil) (1.5 g, 37.5 mmol)portionwise, maintaining the temperature below 5° C. Upon completion ofthe addition, the dark brown solution was stirred at 0-5° C. for 10 minbefore trimethylsilylethyloxymethyl chloride (6.64 ml, 37.5 mmol) wasadded dropwise maintaining the temperature below 5° C. The brownsolution was then warmed to ambient temperature over a 1 hr periodbefore being quenched into water (100 ml). The mixture was thenextracted with ethyl acetate (3×25 ml) and the combined organic extractswere evaporated in vacuo to yield a brown oil. This was purified byflash column chromatography (ethyl acetate:hexane 1:1 as eluant) toyield the subtitle compound (8.96 g, 62%) as a brown oil.

¹H NMR (300 MHz, CDCl₃) δ=0.95 (9H, s), 0.89 (2H, t, J=6.8 Hz),1.42-1.86 (4H, m), 2.14-2.30 (1H, m), 2.35-2.60 (5H, m), 3.05-3.18 (2H,m), 3.42 (2H, t, J=6.8 Hz), 5.41 (2H, s), 7.31 (2H, s), 7.71 (1H, s).LRMS (Thermospray): 424.5 (MH⁺).

(b)N-Benzyl-1-cyano-N-methyl-1-[(R)-3-(1-methyl-2-pyrrolidinylmethyl-1-trimethylsilylethyloxethyl-1H-indol-5-yl]methanesulfonamide

To a stirred slurry of N-benzyl-1-cyano-N-methylmethanesulfonamide (fromstep (a), 1.42 g, 6.33 mmol) and tetrakis(triphenylphosphine)palladium(0) (399 mg, 0.34 mmol) in ethylene glycol dimethylether (5ml)) at 0° C. under a nitrogen atmosphere was added sodium hydride (60%dispersion in mineral oil) (495 mg, 12.4 mmol) portion wise, maintainingthe temperature below 5° C. The brown solution was then warned toambient temperature over a 10 minute period, before a solution of(R)-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1-trimethylsilylethyloxymethyl-1H-indole(see Example 1(c), 2.44 g, 5.8 mmol) in toluene (20 ml) was addeddropwise and the mixture was then warmed to reflux. Reflux wasmaintained for 1.5 hr after which time the dark brown solution wascooled to ambient temperature. The reaction mixture was then poured intowater (50 ml) and extracted with ethyl acetate (3×25 ml). The organicextracts were combined and evaporated in vacuo to yield a brown oil.This was purified by flash column chromatography (ethylacetate:hexane:diethylamine 1:1:0.1 as eluant) to yield the subtitlecompound (3.25 g, 99%) as a brown oil.

¹H NMR (300 MHz, CDCl₃) δ=0.93 (9H, s), 0.88 (2H, t, J=6.8 Hz),1.46-1.90 (4H, m), 2.15-2.30 (1H, m), 2.44 (3H, s), 2.60-2.76 (4H, m),3.05-3.20 (2H, m), 3.45 (2H, t, J=6.8 Hz), 4.20 (2H, s), 5.28, (1H, s),5.45 (2H, s), 7.10 (1H, s), 7.22-7.43 (6H, m), 7.50-7.58 (1H, s), 7.78(1H, s). LRMS (Thermospray): 567 (MH⁺).

(c)(R)-N-Benzyl-N-methyl-1-[3-(1-methyl-2-pyrrolidinylmethyl)-1-trimethylsilylethyloxymethyl-1H-indol-5-yl]methanesulfonamide

To a stirred solution ofN-benzyl-1-cyano-N-methyl-1-[(R)-3-(1-methyl-2-pyrrolidinylmethyl)-1-trimethylsilylethyloxymethyl-1H-indol-5-yl]methanesulfonamide(from step (b), 1.56 g, 2.8 mmol) in ethanol (12 ml) at ambienttemperature was added 2N potassium hydroxide solution (6.24 ml, 12.5mmol). The dark brown solution was then brought to reflux and maintainedat this temperature for 15 hr. The oily reaction mixture was then cooledto ambient temperature and extracted with ethyl acetate (3×25 ml). Theorganic extracts were combined and evaporated in vacuo to yield thecrude product as a dark brown oil. This was purified by flash columnchromatography (ethyl acetate:hexane:dietiylamine 1:1:0.1 as eluant) toyield the title compound (1.49 g, 75%) as a brown oil.

¹H NMR (300 MHz, CDCl₃) δ=0.91 (9H, s), 0.85 (2H, t, J=6.8 Hz),1.48-1.88 (4H, m), 2.15-2.30 (1H, m), 2.36-2.69 (8H, m), 3.05-3.20 (2H,m), 3.45 (2H, t, J=6.8 Hz), 4.20 (2H, s), 4.42 (2H, s), 5.42 (2H, s),7.08 (1H, s), 7.14-7.34 (6H, m), 7.40-7.55 (1H, d), 7.56 (1H, s). LRMS(Thermospray): 542.8 (MH⁺).

EXAMPLE 5(R)-1-[1-Allyl-3-(1-methyl-2-pyrrolidinylmethyl-1H-indol-5yl]-N-diphenylmethyl-N-methylmethanesulfonamide

(a) (R)-1-Allyl-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole

To a stirred solution of(R)-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (22.5 g, 76.8mmol) in tetrahydroflran (132 ml) at 0° C. under a nitrogen atmospherewas added potassium tert-butoxide (9.47 g, 84.4 mmol) portionwise,maintaining the temperature below 5° C. Upon completion of the addition,the dark brown slurry was stirred at 0-5° C. for 30 min before allylbromide (7.3 ml, 84.3 mmol) was added dropwise maintaining thetemperature below 5° C. The brown solution was then warmed to ambienttemperature over a 1 hr period before being quenched into water (100ml). The mixture was then extracted with ethyl acetate (3×25 ml) and thecombined organic extracts were evaporated in vacuo to give a brown oil.This was purified by flash column chromatography (ethylacetate:hexane:diethylamine 1:1:0.1 as eluant) to yield the subtitlecompound (19.94 g, 78%) as a golden oil.

¹H NMR (300 MHz, CDCl₃) δ=1.42-1.92 (4H, m), 2.15-2.35 (1H, m),2.38-2.64 (5H, m), 3.02-3.22 (2H, m), 4.66 (2H, d, J=4.8 Hz), 4.98-5.25(2H, m), 5.88-6.14 (1H, m), 6.39 (1H, s), 7.15 (1H, d, J9.7 Hz), 7.25(1H, d, J=9.7 Hz), 7.72 (1H, s). LRMS (Thermospray): 333 (MH⁺). [α]_(D)+62.90° (c=6, CH₂Cl₂).

(b)1-[(R)-1-Allyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide

To a stirred solution of1-cyano-N-diphenyhmethyl-N-methylmethanesulfonamide (see Example 2(c),1.36 g, 4.5 mmol) in toluene (5 ml) at 0° C. under a nitrogen atmospherewas added sodium hydride (60% dispersion in mineral oil) (345 mg, 8.6mmol) portionwise, maintaining the temperature below 5° C. The darkbrown solution was then warmed to ambient temperature over a 30 minperiod, before tetrakis(triphenylphosphine) palladium(0) (285 mg, 0.25mmol) was added in one portion. A solution of(R)-1-allyl-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (fromstep (a), 1.37 g, 4.1 mmol) in toluene (5 ml) was then added dropwise tothe yellow/green slurry and the mixture was warmed to reflux. Reflux wasmaintained for 2 hr after which time the dark brown solution was cooledto ambient temperature. The reaction mixture was then poured into water(50 ml) and extracted with ethyl acetate (3×25 ml). The organic extractswere combined and evaporated in vacuo to yield a brown oil. This waspurified by flash column chromatography (ethylacetate:hexane:diethylamine 1:1:0.1 as eluant) to yield the subtitlecompound (1.81 g, 80%) as a brown oil.

¹H NMR (300 MHz, CDCl₃) δ=1.42-1.95 (4H, m), 2.16-2.30 (1H, m),2.35-2.66 (4H, m), 2.75 (3H, s), 3.02-3.20 (2H, m), 4.66 (2H, d, J=4.8Hz), 4.95-5.15 (3H, m), 5.16-5.25 (1H, m), 5.86-6.06 (1H, m), 6.43 (1H,s), 6.98 (1H, s), 7.10-7.50 (12H, m), 7.58 (1H, m). LRMS (Thermospray):552.7 (MH⁺).

(c)(R)-1-[1-Allyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-N-diphenylmethyl-N-methylmethanesulfonamide

To a stirred solution of1-[(R)-1-allyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide(from step (b), 5.11 g, 9.25 mmol) in ethanol (10.22 ml) at ambienttemperature was added 2N potassium hydroxide solution (20.4 ml, 41mmmol). The dark brown solution was then brought to reflux andmaintained at this temperature for 15 hr. The oily reaction mixture wasthen cooled to ambient temperature and extracted with ethyl acetate(3×50 ml). The organic extracts were combined and evaporated in vacuo toyield a dark brown oil. This was purified by flash column chromatography(ethyl acetate:hexane:diethylamine 1:1:0.1 as eluant) to yield the titlecompound (3.7 g, 76%) as a brown oil.

¹H NMR (300 MHz, CDCl₃) δ=1.42-1.93 (4H, m), 2.14-2.29 (1H, m),2.34-2.73 (8H, m), 3.01-3.20 (2H, m), 4.27 (2H, s), 4.66 (2H, d, J=4.8Hz), 4.96-5.28 (2H, m), 5.88-6.06 )1H, m), 6.38 (1H, s), 6.88-7.44 (14H,m). LRMS (Thermospray): 528.9 (MH⁺) [α]_(D) +52.7° (c=0.88, CH₂Cl₂).

EXAMPLE 6N-tert-Butyl-1-cyano-N-methyl-1-[(R)-3(1-methyl-2-pyrrolidinylmethyl)-1-tosyl-1H-indol-5-yl]methanesulfonamide

(a) Methyl(N-tert-butyl-N-methylsulfamoyl)acetate

The subtitle compound (14.81 g, 59%) was prepared as a yellow oil fromtert-butylmethylamine (24.48 g, 0.28 mol) and methylchlorosulfonylacetate (19.37 g, 0.11 mmol), using the method of Example1(a).

¹H NMR (300 MHz, CDCl₃) δ=1.42 (9H, s), 2.90 (3H, s), 3.77 (3H, s), 3.97(2H, s).

Found: C, 43.21; H, 7.71; N, 6.31. C₈H₁₇NO₄S requires C, 43.03; H, 7.67;N, 6.27%.

(b) (N-tert-Butyl-N-methylsulfamoyl)acetamide

The subtitle compound (3.66 g, 84%) was prepared as a white solid fromaqueous ammonia solution (10 ml, s.g.=0.88) and methyl(N-tert-butyl-N-methylsulfamoyl)acetate (from step (a), 4.7 g, 21 mmol),using the method of Example 1(b). m.p. 105-109° C.

¹H NMR (300 MHz, CDCl₃) δ=1.47 (9H, s), 2.95 (3H, s), 3.90 (2H, s), 5.50(1H, bs), 6.63 (1H, bs).

Found: C, 40.31; H, 7.70; N, 13.41. C₇H₁₆N₂O₃S requires C, 40.37; H,7.74; N, 13.45%.

(c) N-tert-Butyl-1-cyano-N-methylmethanesulfonamide

The subtitle compound (7.31 g, 96%) was prepared as a yellow oil from(N-tert-butyl-N-methylsulfamoyl)acetamide (from step (b), 8.31 g, 40mmol) using the method of Example 1(c).

¹H NMR (300 MHz, CDCl₃) δ=1.49 (9H, s), 3.07 (3H, s), 3.97 (2H, s).

Found: C, 44.20; H 7.51; N, 14.70. C₇H₁₄N₂O₂S requires C, 44.19; H 7.42;N, 14.72%.

(d) (R)-5-Bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1-tosyl-1H-indole

To a stirred solution of(R)-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (10.0 g, 34.1mmol) in ethyleneglycol dimethylether (50 ml) at 0° C. under a nitrogenatmosphere was added potassium hydroxide flake (9.58 g, 171 mmol) in oneportion. Para-toluenesulfonyl chloride (6.83 g, 35.8 mmol) was thenadded portionwise to the brown slurry over a 5 min period, maintainingthe temperature below 5° C. The brown slurry was then warmed to ambienttemperature and stirred for a further 2 hr. The mixture was thenfiltered in vacuo and the filter cake washed with toluene (2×100 ml).The filtrate was then concentrated in vacuo to approximately 20 mlvolume which resulted in precipitation of a cream solid. After stirringfor 2 hr, the solid was filtered and dried in vacuo at 50° C. for 12 hrto give the title compound (9.91 g, 65%) as a beige solid. m.p. 98-104°C.

¹H NMR (300 MHz, CDCl₃) δ=1.54-1.84 (4H, m), 2.15-2.28 (1H, m),2.30-2.58 (8H, m), 2.90-3.15 (2H, m), 7.15-7.30 (2H, m), 7.35-7.42 (2H,m), 7.58 (1H, m), 7.65-7.9 (3H, m). LRMS (Thermospray) 449.4 (MH⁺).[α]_(D) +52.9° (c=5.1, CH₂Cl₂).

(e)N-tert-Butyl-1-cyano-N-methyl-1-[(R)-3-(1-methyl-2-pyrrolidinylmethyl)-1-tosyl-1H-indol-5-yl]methanesulfonamide

To a stirred suspension of dichlorobis(triphenylphosphine)palladium (II)(704 mg, 1 mmol) and triphenylphosphine (525 mg, 2 mmol) inethyleneglycol dimethylether (5 ml) at ambient temperature under anatmosphere of nitrogen was added sodium borohydride (38 mg, 1 mmol) inone portion. The green slurry was stirred for 5 min, thenN-tert-butyl-cyano-N-methylmethanesulfonamide (from step (c), 1.04 g,5.4 mmol) was added in one portion. The green slurry was then cooled to0-5° C. and sodium hydride (60% dispersion in mineral oil) (441 mg, 11mmol) was added portionwise, maintaining the temperature below 5° C. Thebrown solution was then warmed to ambient temperature over a 10 minperiod, before a solution of(R)-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1-tosyl-1H-indole (fromstep (d), 2.24 g, 5 mmol) in ethyleneglycol dimethyl ether (15 ml) wasadded dropwise. The brown slurry was then warmed to reflux. Reflux wasmaintained for 1.5 hr after which time the dark brown solution wascooled to ambient temperature. The reaction mixture was then poured intowater (20 ml) and extracted with ethyl acetate (3×25 ml). The organicextracts were combined and evaporated in vacuo to yield a brown oil.This was purified by flash column chromatography (ethylacetate:hexane:diethylamine 1:1:0.1 as eluant) to yield the subtitlecompound (1.23 g, 45%) as a golden oil.

¹H NMR (300 MHz, CDCl₃) δ=1.44 (9H, s), 1.54-1.84 (4H, m), 2.15-2.28(1H, m), 2.32-2.66 (8H, m), 2.85 (3H, s), 2.95-3.15 (2H, m), 5.15 (1H,s), 7.18-7.28 (2H, m), 7.39-7.50 (2H, m), 7.62-7.76 (3H, m), 7.96-8.05(1H, s). LRMS (Thermospray): 557.8 (MH⁺).

EXAMPLE 73-[2-(Dimethylamino)ethyl]-N-methy-1H-indole-5-methanesulfonamide

(a) 5-bromo-N,N-dimethyl-α-oxo-1H-indole-3-acetamide

To a solution of 5-bromoindole (15.85 g, 81 mmol) in tetrahydrofuran (80ml) at 0-5° C. under an atmosphere of nitrogen was added oxalyl chloride(7.76 ml 89 mmol) dropwise, maintaining the temperature below 5° C. Thecloudy solution was then warmed to ambient temperature and stirred for30 min, before being re-cooled to 0-5° C. The solution was thensaturated with anhydrous dimethylamine for 30 min, which resulted information of a yellow precipitate. The slurry was then warmed to ambienttemperature and diluted with demineralised water (100 ml) before beingextracted with dichloromethane (3×50 ml). The organic extracts werecombined and evaporated in vacuo to give a white solid. This wasslurried in a mixture of ethyl acetate:hexane (1:1) (40 ml) for 8 hr andthen filtered in vacuo to give the subtitle compound (20.28 g, 85%) as awhite solid. m.p. 189-190° C.

¹H NMR (300 MHz, CDCl₃) δ=2.90 (3H, s), 2.96 (3H, s), 7.35-7.55 (2H, m),8.15 (1H, s), 8.22 (1H, d, J=0.97 Hz).

Found: C, 48.71; H, 3.72; N,9.41. Cl₁₂H₁₁BrN₂O₂ requires C, 48.84; H,3.76; N, 9.49%.

(b) 5-Bromo-3-[2-(dimethylamino)ethyl]-1H-indole

A solution of 5-bromo-N,N-dimethyl-α-oxo-1H-indole-3-acetamide (fromstep (a), 19.85 g, 67.3 mmol) in tetrahydrofuran (100 ml) was addeddropwise to a slurry of lithium aluminium hydride (7.66 g, 0.2 mol) intetrahydrofuran (20 ml) under a nitrogen atmosphere, maintaining thetemperature below 5° C. The yellow green slurry was then warmed toambient temperature and then brought to gentle reflux. Reflux wasmaintained for 5 hr after which time the reaction mixture was cooled to0° C. and isopropyl alcohol (150 ml) and IMS (150 ml) were addedsequentially. The grey slurry was then warmed to ambient temperature,before 1N NaOH (100 ml) was added. The reaction mixture was thenfiltered through a celite (trade mark) pad and the pad washedconsecutively with demineralised water (100 ml) and IMS (100 ml). Thefiltrate was then concentrated under reduced pressure until all alcoholhad been removed and then the aqueous residue was extracted with ethylacetate (2×200 ml). The combined organic extracts were then evaporatedin vacuo to give a brown oil. This was triturated with a mixture ofhexane and ethyl acetate (1:1) (30 ml) to give the subtitle compound(13.4 g, 75%) as a cream solid. m.p. 82-85° C.

¹H NMR (300 MHz, CDCl₃) δ=2.34 (6H, s), 2.62 (2H, t, J=7.8 Hz), 2.90(2H, t, J=7.8 Hz), 7.0, (1H, s), 7.1-7.35 (2H, m), 7.72 (1H, s), 8.26(1H, bs).

Found: C, 53.94; H, 5.61; N, 10.40. C₁₂H₁₅BrN₂ requires C, 53.95; H,5.66; N, 10.49%.

(c) 1-Benzyl-5-bromo-3-[2-(dimethylamino)ethyl]-1H-indole

To a stirred solution of1-Benzyl-5-bromo-3-[2-(dimethylamino)ethyl]-1H-indole (from step (b),10.18 g, 38.1 mmol) in tetrahydrofuran (50 ml) at 0° C. under a nitrogenatmosphere was added sodium hydride (60% dispersion in mineral oil)(1.68 g, 42 mmol) portionwise, maintaining the temperature below 5° C.Upon completion of the addition, the dark brown solution was stirred at0-5° C. for 1 hr before benzyl bromide (4.99 ml, 42 mmol) was addeddropwise maintaining the temperature below 5° C. The brown solution wasthen warmed to ambient temperature over a 1 hr period before beingquenched into water (100 ml). The mixture was then extracted with ethylacetate (3×25 ml) and the organic extracts were combined and evaporatedin vacuo to yield a brown oil. This was purified by flash columnchromatography (ethyl acetate:hexane:diethylamine 1:1:0.1 as eluant) togive the subtitle compound (7.07 g, 52%) as a white solid. m.p. 49-50°C.

¹H NMR (300 MHz, CDCl₃) δ=2.34 (6H, s), 2.60 (2H, t, J=7.8 Hz), 2.89(2H, t, J=7.8 Hz), 5.23 (2H, s), 6.95, (1H, s), 7.01-7.40 (7H, m), 7.72(1H, m).

Found: C, 63.69; H, 5.93; N, 7.76. C₁₉H₂₁BrN₂ requires C, 63.87; H,5.92;N, 7.84%.

(d)1-[1-Benzyl-3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide

To a stirred solution of1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide (see Example 2(c),2.36 g, 7.9 mmol) in a mixture of toluene (4 ml) and ethylene glycoldimethylether (1 ml) at 0-5° C. under a nitrogen atmosphere was addedsodium hydride (60% dispersion in mineral oil) (577 mg, 14.4 mmol)portionwise, maintaining the temperature below 5° C. Upon completion ofthe addition, the dark brown solution was warmed to ambient temperatureover a 30 min period, before tetrakis(triphenylphospline) palladium(0)(529 g, 0.46 mmol) was added in one portion. A solution of1-benzyl-5-bromo-3-[2-(dimethylamino)ethyl]-1H-indole (from step (c),2.34 g, 6.6 mmol) in toluene (2 ml) was then added dropwise to the brownslurry and the mixture was warmed to reflux. Reflux was maintained for 2hr after which time the dark brown solution was cooled to ambienttemperature. The reaction mixture was then poured into water (25 ml) andextracted with ethyl acetate (3×5 ml). The organic extracts werecombined and evaporated in vacuo to yield a brown oil. This wasre-dissolved in absolute ethanol (8 ml) and stirred for 18 hr over whichtime precipitation occurred. The solid was filtered and dried in vacuoat 50° C. overnight to yield the subtitle compound (1.3 g, 35%) as acream solid. m.p. 98-100° C.

¹H NMR (300 MHz, CDCl₃) δ=2.30 (6H, s), 2.52 (2H, m), 2.75 (3H, s),2.80-2.92 (2H, m), 4.96 (1H, s), 5.24 (2H, s), 6.39 (1H, s), 6.94-7.75(19H, m).

Found: C, 72.56; H, 6.29; N, 9.31. C₃₅H₃₆N₄O₂S requires C, 72.89; H,6.29; N, 9.71%.

(e)1-[1-Benzyl-3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-N-diphentlmethyl-N-methylmethanesulfonamide

To a stirred solution of1-[1-benzyl-3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-1-cyano-N-diphenylmethyl-N-methylmethanesulfonarmide(from step (d), 3.01 g, 5.2 mmol) in IMS (15 ml) at ambient temperaturewas added 2N potassium hydroxide solution (15 ml, 30 mmol). The darkbrown solution was then brought to reflux and maintained at thistemperature for 15 hr. The oily reaction mixture was then cooled toambient temperature and extracted with ethyl acetate (3×100 ml). Theorganic extracts were combined arid evaporated in vacuo to yield thecrude product as a dark brown oil. This was purified by flash columnchromatography (ethyl acetate:hexane:diethylamine 1:1:0.1 as eluant) toyield the subtitle compound (2.14 g, 74%) as a pale yellow solid. m.p.98-100° C.

¹H NMR (300 MHz, CDCl₃) δ=2.35 (6H, s), 2.54-2.65 (5H, m), 2.85 (2H, t,J=8.7 Hz), 4.27 (2H, s), 5.24 (2H, s), 6.35 (1H, s), 6.94-7.43 (19H, m).

Found: C, 74.47; H, 6.44; N, 7.79. C₃₄H₃₇N₃O₂S requires C, 74.01; H,6.76; N, 7.62%.

(f) 3-[2-(Dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide

To a stirred slurry of calcium turnings (243 mg, 6 mmol) intetrahydrofuran (4 ml) at −40° C. was condensed liquid ammonia (4 ml).The blue bronze was stirred at −50 to −40° C. for a further 15 min,before a solution of1-[1-benzyl-3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-N-diphenylmethyl-N-methylmethanesulfonamide(from step (e), 836 mg, 1.5 mmol) in tetrahydrofuran (2 ml) was addeddropwise, maintaining the temperature below −40° C. The dark bluesolution was stirred at −40° C. for a further 30 minutes, beforesaturated ammonium chloride solution (10 ml) was added dropwise and thegrey solution warmed to ambient temperature. Water (10 ml) was thenadded and the white slurry stirred for 15 min, before being filtered invacuo. The solid was then dissolved in 5N HCl (12 ml) and the resultingorange solution extracted with ethyl acetate (10 ml). The pH of theaqueous phase was then adjusted (pH=10) with 10N NaOH which resulted inprecipitation. The solid was filtered and dried in vacuo at 50° C.overnight to yield the title compound (250 mg, 56%) as a white solid.m.p. 159-163° C.

¹H NMR (300 MHz, CDCl₃) δ=2.22 (6H, s), 2.53-2.61 (5H, m), 2.75-2.89(2H, m)4.33 (2H, s), 6.75 (1H, q, J=3 Hz), 7.05 (1H, d, J=4.85 Hz), 7.15(1H, s), 7.30 (1H, d, J=Hz), 7.50 (1H, s), 10.8 (1H, bs). LRMS(thermospray) 296.4 (MH⁺)

What is claimed is:
 1. A compound of formula I

wherein R¹ and R² independently represent N-protecting groups stable tobasic hydrolysis conditions and removable by hydrogenolysis; and R³represents a C₁₋₆ alkyl group substituted by: (i) a 5- or 6-memberednitrogen-containing saturated heterocyclic group which in turn may besubstituted by C₁₋₆ alkyl or a pyrimidine ring which is itselfsubstituted by C₁₋₆ alkoxy; or (ii) di(C₁₋₆ alkyl)amino.
 2. A compoundof formula III

wherein R¹ is an N-protecting group stable to basic hydrolysisconditions and removable by hydrogenolysis.
 3. A compound of formula IV

wherein R¹ and R² independently represent N-protecting groups stable tobasic hydrolysis conditions and removable by hydrogenolysis; and R³represents a C₁₋₆ alkyl group substituted by: (i) a 5- or 6-memberednitrogen-containing saturated heterocyclic group which in turn may besubstituted by C₁₋₆ alkyl or a pyrimidine ring which is itselfsubstituted by C₁₋₆ alkoxy; or (ii) di(C₁₋₆ alkyl)amino.
 4. A processfor the production of a compound of formula I,

wherein R¹ and R² independently represent N-protecting groups stable tobasic hydrolysis conditions and removable by hydrogenolysis; and R³represents a C₁₋₆ alkyl group substituted by: (i) a 5- or 6-memberednitrogen-containing saturated heterocyclic group which in turn may besubstituted by C₁₋₆ alkyl or a pyrimidine ring which is itselfsubstituted by C₁₋₆ alkoxy; or (ii) di(C₁₋₆ alkyl)amino; which comprisesreacting a compound of formula II,

wherein Hal represents Cl, Br or I; and R² and R³ are as defined above;with a compound of formula III,

wherein R¹ is as defined above; in the presence of a strong base and apalladium(0) catalyst, at an elevated temperature, in a solvent whichdoes not adversely affect the reaction.
 5. A process as claimed in claim4, wherein the strong base is sodium hydride or potassium t-butoxide. 6.A process according to claim 4, wherein the palladium(0) catalyst istetrakis(triphenylphosphine)palladium(0).
 7. A process according toclaim 4, wherein the solvent is a mixture of toluene and ethyleneglycol-dimethylether.
 8. A process as claimed in claim 4, wherein Hal isBr.
 9. A process for the production of a compound of formula V,

wherein R³ is as defined in claim 4; which comprises: (i) basichydrolysis of the cyano group of a compound of formula I as defined inclaim 1, followed by decarboxylation of the resulting carboxylic acid,to provide a compound of formula IV,

wherein R¹⁻³ are as defined in claim 4; followed by (ii) replacement ofR¹ and R² with H.
 10. A process as claimed in claim 9, wherein step (i)is carried out using aqueous potassium hydroxide in ethanol at anelevated temperature.
 11. A process according to claim 9, wherein step(ii) is carried out using hydrogenolysis.
 12. A process according toclaim 4 or claim 9, wherein R¹ represents benzyl, CH₂OCH₂(C₆H₅),CH(C₆H₅)₂ or t-butyl.
 13. A process according to claim 4 or claim 9,wherein R² represents an N-protecting group which is stable to basichydrolysis conditions.
 14. A process as claimed in claim 13, wherein R²represents benzyl or CH₂OCH₂(C₆H₅).
 15. A process according to claim 4or claim 9, wherein R³ represents CH₂CH₂N(CH₃)₂ or a group of formula Iaor Ib,